Octapeptide bombesin analogs

A therapeutic peptide comprising between seven and ten amino acid residues, inclusive, said peptide being an analog of one of tLe following naturally occurring peptides terminating at the carboxy-terminus with a Met residue:

• (a) litoein;
• (b) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide;
• and (c) the ten amino acid carboxy-terminal region of amphibian bombesin;
• said therapeutic peptide being of the formula:
• wherein
• A0=Gly, Nle, α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO2, OH, H or CH3), Trp, Cys, or β-Nal, or is deleted;
• A1=the D or L-isomer of any of pGlu, Nle, or α-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO2, OH, H or CH3), F5-Phe, Trp, Cys, or B-Nal, or is deleted;
• A2=pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Ci, Br, NO2, OH, H or CH3), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
• A4=Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO2, OH, H or CH3), Trp, Cys, or β-Nal;
• A5=Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Ci, Br, OH, H or CH3), Trp, Thr, or β-Nal;
• A6=Sar, Gly, or the D-isomer of any of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO2, OH, H or CH3), Trp, Cys, or β-Nal;
• A7=1-methyl-His, 3-methyl-His, or His;
• provided that, if A0 is present, A1 cannot be pGlu;
• further provided that, if A0 or A1 is present, A2 cannot be pGlu;
• further provided that, when A0 is deleted and A1 is pGlu, R1 must be H and R2 must be the portion of Glu that forms the imine ring in pGlu;
• and further provided that, W can be any one of the following:
• wherein R3 is CHR20—(CH2)n1 (where R20 is either of H or OH;
• and. n1 is either of 1 or 0), or is deleted, and Z1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, Gln, p-X-Phe (where X=H, F, Cl, Br, NO2, OH, or CH3), F5-Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-nal;
• and V is either OR4, or
• where R4 is any of C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl, or C7-10 phenylalkyl, and each R5, and R6, independently, is any of H, C1-12 alkyl, C7-10 phenylalkyl, lower acyl, or,
• where R22 is any of H, C1-12 alkyl, C7-10 phenylalkyl, or lower acyl;
• provided that, when one of R5 or R6 is —NHR22, the other is H;
• wherein Z1 is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO2, OH or CH3), F5-Phe, Trp, Cys, Met, Pro, or HyPro;
• and each Z2, Z3, and Z4, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl;
• or
• wherein each Z20 and Z30, independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl;
• further provided that, when either of Z20 or Z30 is other than H, A7 is His, A6 is Gly, A5 is Val, A4 is Ala, A2 is His, and either of R1 or R2 is other than H, A1 must be other than deleted;
• further provided that, for the formulas (I) through (III) any asymmetric carbon atom can be R, S or a racemic mixture;
• and further provided that each R1 and R2, independently, is H, C1-12 alkyl, C7-10 phenylalkyl, COE1 (where E1 is C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl, or C7-10 phenylalkyl), or lower acyl, and R1 and R2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R1 or R2 is COE1, the other must be H, or a pharmaceutically acceptable salt thereof.